Convulsant seizures occur in various chronic central nervous system (CNS) disorders, particularly epilepsies. These seizures are generally correlated with abnormal and excessive EEG (electroencephalogram) discharges. A variety of drugs have been used for treatment of these seizures. Many of the older drugs are structurally related to phenobarbital, for example, the hydantoins, the deoxybarbiturates, the oxazolidinediones and the succinimides. More recently developed anticonvulsant compounds include the benzodiazepines, iminostilbenes, and valproic acid. (Porter R J, Meldrum B S (1992) "Antiepileptic drugs" Basic & Clinical Pharmacology, Katzung B G, Ed., Appleton & Lange, Norwalk, Connecticut, 5th Edition, pp.331-349.) Additional compounds, containing various types of chemical structures and having various pharmacological mechanisms of action are being developed because of their anticonvulsant activities. (Trevor A J, Way W L (1992) "Sedative-hypnotics" Basic & Clinical Pharmacology, Katzung B G, Ed., Appleton & Lange, Norwalk, Connecticut, 5th Edition, pp.306-319.)
Some drugs which have anticonvulsant activities are also useful for the relief of anxiety, i.e., as anxiolytic agents. In particular, the benzodiazepines are useful for this purpose. These drugs can be used to ameliorate both situational anxiety and certain disease-associated anxiety conditions. Anxiolytic agents, having sedative-hypnotic actions are also widely used for the treatment of insomnia. (Loscher W, Schmidt D (1994) "Strategies in antiepileptic drug development: Is rational drug design superior to random screening and structural variation" Epilepsy Res., 17, 95-134.)
The pharmacological mechanisms of actions of anticonvulsant and anxiolytic drugs are complex. One pharmacological mechanism of action of these agents is the ability to enhance the action of .gamma.-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, at GABAA receptors. The anticonvulsant and/or anxiolytic activities of clinically-useful drugs including benzodiazepines and barbiturates are correlated with their enhancement of this GABAergic activity. (Porter R J, Meldrum B S (1992) supra; Trevor A J, Way W L (1992) supra; Loscher W, Schmidt D (1994) supra.) Potentiation or enhancement of GABA function is assessed, for example, by measuring chloride ion current enhancement in cultured rat hippocampal and spinal cord neurons.
Analogs of .alpha.-alkyl substitued .gamma.-butyrolactones and .alpha.-alkyl substituted .gamma.-thiobutyrolactones are reported to have anticonvulsant activity. The thiobutyrolactones are reported to be more active than the butyrolactone analogs, with .alpha.-ethyl-.alpha.-methyl-.gamma.-thiobutyrolactone reported to have the strongest activity. (Levine J A, Ferrendelli J A, Covey D F (1986) "Alkyl-substituted thiolo-, thiono-, and dithio-.gamma.-butyrolactones: New classes of convulsant and anticonvulsant agents" J. Med. Chem., 29 1996-1999; Ferrendelli J A, Holland K D, McKeon A C, Covey D F (1989) "Comparison of the anticonvulsant activities of ethosuximide, valproate, and a new anticonvulsant, thiobutyrolactone" Epilepsia, 30, 617-622; Holland K D, McKeon A C, Covey D F, Ferrendelli J A (1990) "Binding interactions of convulsant and anticonvulsant .gamma.-butyrolactones and .gamma.-thiobutyrolactones with the picrotoxin receptor" J. Pharmacol. Exp. Ther., 254, 578-583; Holland K D, Ferrendelli J A, Covey D F, Rothman S M (1990) "Physiological regulation of the picrotoxin receptor by .gamma.-butyrolactones and .gamma.-thiobutyrolactones in cultured hippocampal neurons" J. Neuroscience, 10, 1719-1727; Holland K D, Yoon K-W, Ferrendelli J A, Covey D F, Rothman S M (1991) ".gamma.-Butyrolactone antagonism of the picrotoxin receptor: Comparison of a pure antagonist and a mixed antagonist/inverse agonist" Mol. Pharmacol., 39, 79-84; Yoon K-W, Canney D J, Covey D F, Rothman S M (1990) "Modulation of the picrotoxin receptor by fluorinated ethyl, methyl-butyrolactones" J. Pharmacol. Exp. Ther., 255, 248-255; Canney D J, Holland K D, Levine J A, McKeon A C, Ferrendelli J A, Covey D F (1991) "Synthesis and structure-activity studies of alkyl-substituted .gamma.-butyrolactones and .gamma.-thiobutyrolactones: ligands for the picrotoxin receptor" J. Med. Chem., 34, 1460-1467; Holland K D, McKeon A C, Canney D J, Covey D F, Ferrendelli J A (1992) "Relative anticonvulsant effects of GABAmimetic and GABA modulatory agents" Epilepsia, 33, 981-986; Holland K D, Bouley M G, Covey D F, Ferrendelli J A (1993) "Alkyl-substituted .gamma.-butyrolactones act at a distinct site allosterically linked to the TBPS/picrotoxinin site on the GABAA receptor complex" Brain Res., 615, 170-174.) EP patent application 151,964 (Tessitore P T, published 1985) reports .alpha.-amino-.gamma.-butyrolactone derivatives, for example .alpha.-n-butylcarbonyl-amino-.gamma.-butyrolactone, having anticonvulsant, anti-epileptic, sedative action and ability to inhibit the ingestion of alcohol.
U.S. Pat. No. 5,010,079 (Masoury P et al., issued Apr. 4, 1991) reports indolone derivatives useful in the treatment of anxiety, depression and schizophrenia.
In contrast to the properties of the lactones and thiolactones discussed above, 3,3-dimethyl-2-pyrrolidinone (.alpha.,.alpha.-dimethyl-.gamma.-butyrolactam) was reported to display no anticonvulsant activity and 4-ethyl-4-methyl-2-pyrrolidinone (.beta.-ethyl-.beta.-methyl-.gamma.-butyrolactam) was reported to be "much less active" by the convulsant and anticonvulsant criteria used compared to lactone analogs. (Klunk W E, Covey D F, Ferrendelli J A (1982) "Structure-Activity Relationships of Alkyl-Substituted .gamma.-Butyrolactones and Succinimides" Mol. Pharmacol. 22 p. 444-450). Further, 3,3-Diethyl-2-piperidinone was reported to have weak sedative activity, a property undesirable in anticonvulsants and anxiolytics, in mice at a dose of 100 mg/kg. (Baker J A and Harper J F (1967) "The Synthesis of 3,3-Diethylpiperid-2-one" J. Chem. Soc. (C) p. 2148)
This invention is based in part on the inventors'finding that certain 3-mono- and 3,3-disubstituted lactams, in contrast to the reported lack of function in a 3,3-dimethyl lactam, do significantly enhance GABA neuronal inhibition and are significantly more active anticonvulsant and anxiolytic agents than prior art lactones and thiolactones. Further, these lactams have been found to have relatively low toxicity and low sedative activity.
Several 2-pyrrolidinone and 2-piperidinone derivatives have been reported:
3-methyl-2-pyrrolidinone (Menezes R, Smith M B (1988) "A mild and facile root to .omega.-amino esters" Syn. Commun., 18, 1625-1636; Khoukhi N, Vaultier M, Carrie, R (1987) "Synthesis and reactivity of methyl .gamma.-azidobutyrates and ethyl .delta.-azidovalerates and of the corresponding acid chlorides as useful reagents for the aminoalkylation" Tetrahedron, 43, 1811-1822; Adams R, Fles D (1959) "The absolute configuration of the C1 atom in retronecanone (1-methyl-7-oxopyrrolizidine" J. Am. Chem. Soc., 81, 4946-4951.); PA0 3-ethyl-2-pyrrolidinone (Kametani T, Ihara M, Honda T (1970) "Alkaloids of Corydalis pallida var tenuis and the structures of pallidine and kikemanine" J. Chem. Soc. C, 1060-1064; Cummings WAW, Davis AC (1964) "The synthesis and rearrangement of 3-vinyl-2-pyrrolidone" J. Chem. Soc., 4591-4604; Brunner O, Heck-Bleckmann Chr (1951) "Uber das 3-athylpyrrolidin und einige derivate" Monatsh., 82, 371-376.); PA0 3-(2-methylpropyl)-2-pyrrolidinone (Geurtis L H, Meyer P J N "2-Pyrrolidinones" Ger. Offen. 2,609,209 Sep. 16, 1976 and Chem. Abstr. (1977) 86, 29622r); PA0 3-butyl-2-pyrrolidinone (Sinnerich J, Elad D (1968) "The light-induced addition of 2-pyrrolidinone to olefins" Tetrahedron, 24, 4509-4516); PA0 3-phenylmethyl-2-pyrrolidinone; (Menezes R. Smith MB (1988) supra; Bentz G, Besbes N, Laurent A, Stamm H (1987) "Intramolecular radical trapping in SET ring opening of N-(enoyl)aziridines. A new mechanistic probe and a new synthesis of pyrrolidones" Tetrahedron Lett., 28, 2511-2512; Werry J, Stamm H, Lin P Y, Falkenstein R, Gries S, Irngartnger H (1989) "Reactions with aziridines. Part 50. Homolytic aziridine ring opening (aza variant of cyclopropylcarbinyl-homoallyl rearrangement) by addition of tributyltin radical to N-acylaziridines. Factors contributing to the regioselectivity" Tetrahedron, 45, 5015-5028); and PA0 3,3-dimethyl-2-pyrrolidinone (Stamm H, Woderer A, Wiesert W (1981) "Reactions with aziridines. XXII. One step synthesis of pyrrolidones by amidoethylation of simple esters with N-acylaziridines" Chem. Ber., 114, 32-48; Kricheldorf EIR (1975) "Reactions with silylazides. 7. Trimethylsilyl 4-isocyanato-carboxylates and 4-aminocarboxylic acid N-carboxylic acid anhydrides" Makromol. Chem., 176, 57-79.) PA0 2-Piperidinone derivatives previously reported are as follows: PA0 3-methyl-2-piperidinone (Khoukhi N, Vaultier M, Carrie, R (1987) supra); 3-ethyl-2-piperidinone (Koelsch CF (1943) "Synthesis of 3-alkylpiperidones" J. Am. Chem. Soc., 65, 2458-2459); 3-propyl-2-piperidinone (Wang CHJ, Stroupe SD, Jolley ME "Fluorescent polarization immunoassay utilizing substituted triazinylaminofluoresceins" U.S. Pat. No. 4,420,568 Dec. 13, 1983); 3-(2-methylpropyl)-2-piperidinone (Rodriguez M, Heitz A, Martinez J (1992)"`Carba` peptide bond surrogates. Different approaches to Gly- (CH2-CH2)-D,L-Xaa pseudo-dipeptide units" Int. J. Peptide Protein Res. 39, 273-277); 3-phenylmethyl-2-piperidinone; (ld.; Carter PA, Singh S "Preparation of di- and trisubstituted piperidines, morpholines, and bromopiperidines as agrochemical fungicides" Eur. Pat. Appl. EP 435,387. Jul. 3, 1991.); 3,3-dimethyl-2-piperidinone (Mileo JC, Sillion B, De Gaudemaris G. "3,3-Dimethyl-2-piperndinone" Fr. 1,527,755, Jun. 7, 1968); and 3,3-diethyl-2-piperidinone (Baker J A, Harper J F (1967) "Synthesis of 3,3-diethylpiperid-2-one" J. Chem. Soc., C, 2148.) PA0 3-(p-fluorophenylmethyl)-2-pyrrolidinone, 3-(p-fluorophenylmethyl)-2-piperidinone, 3-(p -fluorophenylmethyl)-3-methyl-2-pyrrolidinone, 3-(p-fluorophenylmethyl)-3-methyl-2-piperidinone; PA0 3-n-propyl-2-pyrrolidinone, 3-isopropyl-2-pyrrolidinone, 3-tert-butyl-2-pyrrolidinone, 3-n -butyl-2-pyrrolidinone, 3-sec-butyl-2-pyrrolidinone, 3-n-propyl-2-piperidinone, 3-isopropyl -2-piperidinone, 3-tert-butyl-2-piperidinone, 3-n-butyl-2-piperidinone, 3-sec-butyl-2-piperidinone; PA0 3,3-diethyl-1-methyl-2-pyrrolidinone, 3-ethyl-1-methyl-3-phenylmethyl-2-pyrrolidinone, 1,3-dimethyl-3-phenylmethyl -2-pyrrolidinone, 1-methyl-3-phenylmethyl-2-pyrrolidinone, 3,3-diethyl-1-methyl-2-piperidinone, 3-ethyl-1-methyl-3-phenylmethyl-2-piperidinone, 1,3-dimethyl-3-phenylmethyl-2-piperidinone, 1-methyl-3-phenylmethyl-2-piperidinone, 3-ethyl -1,3-dimethyl piperidinone; PA0 3,3-diethyl-1-phenymethyl-2-pyrrolidinone, 1,3-diphenylmethyl-3-ethyl-2-pyrrolidinone, 1,3-diphenylmethyl-3-methyl-2-pyrrolidinone, 1,3-diphenylmethyl-2-pyrrolidinone, 3,3-diethyl-1-phenylmethyl-2-piperidinone, 1,3-diphenylmethyl-3-ethyl-2-piperidinone, 1,3-diphenylmethyl-3-methyl-2-piperidinone, 1,3-diphenylmethyl-2-piperidinone, 3-ethyl-3-methyl-1-phenylmethyl-2-piperidinone; PA0 4,4-diethyl-2-pyrrolidinone, 4-ethyl-4-phenylmethyl-2-pyrrolidinone, 4-methyl-4-phenylmethyl-2-pyrrolidinone, 4-phenylmethyl-2-pyrrolidinone, 4,4-diethyl-2-piperidinone, 4-ethyl-4-phenylmethyl-2-piperidinone, 4-methyl-4-phenylmethyl-2-piperidinone and 4-phenylmethyl-2-piperidinone, 4-ethyl-4-isopropyl-2-pyrrolidinone; 4-ethyl-4-iso-propyl-2-piperidinone; 4-isopropyl-4-phenylethyl-2-piperidinone; 4-ethyl-4-methyl-2-piperidinone. PA0 4,4-diethyl-1-phenymethyl-2-pyrrolidinone, 1,4-diphenylmethyl-4-ethyl-2-pyrrolidinone, 1,4-diphenylmethyl-4-methyl-2-pyrrolidinone, 1,4-diphenylmethyl-2-pyrrolidinone, 4,4-diethyl-1-phenylmethyl-2-piperidinone, 1,4-diphenylmethyl-4-ethyl-2-piperidinone, 1,4-diphenylmethyl-4-methyl-2-piperidinone, 1,4-diphenylmethyl-2-piperidinone, 4-ethyl-4-methyl-1-phenylmethyl-2-piperidinone; PA0 3,3-diethyl-2-pyrrolidinethione, 3-ethyl-3-phenylmethyl-2-pyrrolidinethione, 3-methyl-3-phenylmethyl-2-pyrr olidinethione, 3-phenylmethyl-2-pyrrolidinethione, 3,3-diethyl-2-piperidinethione, 3-ethyl-3-phenylmethyl-2-piperidinethione, 3-methyl-3-phenylmethyl-2-piperidinethione, 3-phenylmethyl-2-piperidinethione. PA0 4,4-diethyl-2-pyrrolidinethione, 4-ethyl-4-phenylmethyl-2-pyrrolidinethione, 4-methyl-4-phenylmethyl-2-pyrr olidinethione, 4-phenylmethyl-2-pyrrolidinethione, 4,4-diethyl-2-piperidinethione, 4-ethyl-4-phenylmethyl-2-piperidinethione, 4-methyl-4-phenylmethyl-2-piperidinethione, 4-phenylmethyl-2-piperidinethione
EP patent application 435,387 (Carter P A and Singh S, published 1991) reports the formula: ##STR1## where W is --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --, P is --CH.sub.2 --R.sup.1 or CH.sub.2 --CH.sub.2 --R.sup.1 and where R.sup.2 represents a hydrogen or an optionally substituted alkyl group and R' represents optionally substituted alkyl, phenyl, benzyl, or cycloalkyl group as potential intermediates in the synthesis of piperidine derivatives that are useful as fungicides.
All of the references cited in this specification are incorporated in their entirety by reference herein.
None of these 2-pyrrolidinone or 2-piperidinone derivatives were reported to enhance GABA-mediated chloride currents at GABA.sub.A receptors or to have anticonvulsant or anxiolytic activity.